Thyroid Hormone Transport Proteins

Bartalena, Luigi; Robbins, Jacob

doi:10.1016/s0272-2712(18)30427-x

Cited by 131 publications

(94 citation statements)

References 59 publications

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“…That tafamidis occupies the T 4 -binding sites in TTR raises the concern of thyroid metabolic effects; however, <1% of circulating TTR in the blood carries thyroxine because the primary carrier in blood is thyroxine-binding globulin (56)(57)(58). Consistent with these observations, tafamidis was well tolerated by patients, showing no clinically relevant effects on laboratory measures, including thyroid function (59).…”

Section: Discussionmentioning

confidence: 73%

Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade

Bulawa

Connelly²,

DeVit³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

594

605

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The transthyretin amyloidoses (ATTR) are invariably fatal diseases characterized by progressive neuropathy and/or cardiomyopathy. ATTR are caused by aggregation of transthyretin (TTR), a natively tetrameric protein involved in the transport of thyroxine and the vitamin A–retinol-binding protein complex. Mutations within TTR that cause autosomal dominant forms of disease facilitate tetramer dissociation, monomer misfolding, and aggregation, although wild-type TTR can also form amyloid fibrils in elderly patients. Because tetramer dissociation is the rate-limiting step in TTR amyloidogenesis, targeted therapies have focused on small molecules that kinetically stabilize the tetramer, inhibiting TTR amyloid fibril formation. One such compound, tafamidis meglumine (Fx-1006A), has recently completed Phase II/III trials for the treatment of Transthyretin Type Familial Amyloid Polyneuropathy (TTR-FAP) and demonstrated a slowing of disease progression in patients heterozygous for the V30M TTR mutation. Herein we describe the molecular and structural basis of TTR tetramer stabilization by tafamidis. Tafamidis binds selectively and with negative cooperativity (K d s ∼2 nM and ∼200 nM) to the two normally unoccupied thyroxine-binding sites of the tetramer, and kinetically stabilizes TTR. Patient-derived amyloidogenic variants of TTR, including kinetically and thermodynamically less stable mutants, are also stabilized by tafamidis binding. The crystal structure of tafamidis-bound TTR suggests that binding stabilizes the weaker dimer-dimer interface against dissociation, the rate-limiting step of amyloidogenesis.

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Section: Discussionmentioning

confidence: 73%

Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade

Bulawa

Connelly²,

DeVit³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

594

605

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“…Most of the thyroid hormone circulates bound to serum proteins, only 0.3% of T3 and 0.03% of T4 are free in solution [83] [84]. This is reflected in the half-lives of the hormones: T3 has a halve life of about 24 hours, and T4 has a halve life of about 6 to 7 days [84].…”

Section: Thyroid Hormone Transportmentioning

confidence: 99%

Comprehensive Review of Thyroid Embryology, Anatomy, Histology, and Physiology for Surgeons

Arrangoiz¹,

Cordera²,

Caba³

et al. 2018

IJOHNS

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Emil Theodor Kocher and Theodor Billroth pioneered the surgical management of thyroid disease. Their surgical techniques, knowledge of thyroid anatomy, embryology, histology, physiology, and antisepsis practices transitioned a life-threatening operation to one with acceptable morbidity. The modern head and neck surgeon should have a meticulous surgical technique, combined with a thorough understanding of thyroid embryology and anatomy that is central to the understanding and treatment of the different disease processes of the thyroid gland and the consequences of thyroid gland surgery. In this manuscript we will be examining thyroid gland embryology, anatomy, histology, and physiology that is essential to the practicing thyroid surgeon.

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“…An example of a comparable situation is that of thyroid hormone in human plasma, in its T3 and T4 forms. Although T4 predominates, as ϳ99% of detected total thyroid hormone, the active form at the nuclear receptor is actually T3, and T4 is essentially inactive unless modified (31). Similarly, for ascorbic acid and DHA, there is a potential discrepancy between the dominant substrate found and the dominant substrate transported in vivo (2).…”

Section: -Bromo-6-deoxy-l-ascorbic Acidmentioning

confidence: 99%

6-Bromo-6-deoxy-l-ascorbic Acid

Corpe

Lee

Kwon

et al. 2005

Journal of Biological Chemistry

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Vitamin C intracellular accumulation is mediated by Na؉ -dependent vitamin C transporters SVCT1 and -2 and dehydroascorbic acid transporters GLUT1 and -3. It is unclear which pathways dominate in vivo. As a new step to resolve this issue, we identified and tested 6-bromo-6-deoxy-L-ascorbic acid as a specific candidate for SVCTs. In high performance liquid chromatography and electron paramagnetic resonance analyses, the reduced compounds ascorbic acid and 6-bromo-6-deoxy-L-ascorbic acid were similar. The oxidized products 6-bromo-6-deoxy dehydroascorbic acid (BrDHA) and dehydroascorbic acid (DHA) had comparable stabilities, based on reduction recoveries. Upon expression of GLUT1 or GLUT3 in Xenopus oocytes, BrDHA was neither transported nor bound, in contrast to robust transport of DHA. The findings were not explained by differences in the oocyte reduction of DHA and BrDHA because lysed oocytes reduced both compounds equally. Further, there was no transport of the reduced compound, 6-bromo-6-deoxy-L-ascorbic acid, by GLUT1 or GLUT3. As a prerequisite for investigating 6-bromo-6-deoxy-L-ascorbic acid transported by SVCTs, SVCT2 transport activity in oocytes was enhanced 14-fold by construction and use of a vector that added a fixed poly(A) tail to the 3 end of cRNA. For SVCT1 and SVCT2 expressed in oocytes, similar K m and V max values were observed for ascorbic acid and 6-bromo-6-deoxy-Lascorbic acid. In human fibroblasts, predicted to have SVCT-mediated ascorbate accumulation, K m and V max values were again comparable for ascorbic acid and 6-bromo-6-deoxy-L-ascorbic acid. Using activated human neutrophils, predicted to have ascorbate accumulation mediated predominantly by DHA and GLUT transporters, 6-bromo-6-deoxy-L-ascorbic acid accumulation was <1% of accumulation when compared with ascorbic acid. We conclude that 6-bromo-6-deoxy-L-ascorbic acid is the first transport substrate identified as completely specific for SVCTs, but not GLUTs, and provide a new strategy to determine the contribution of each pathway to ascorbate accumulation.

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Thyroid Hormone Transport Proteins

Cited by 131 publications

References 59 publications

Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade

Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade

Comprehensive Review of Thyroid Embryology, Anatomy, Histology, and Physiology for Surgeons

6-Bromo-6-deoxy-l-ascorbic Acid

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